The group of pathologies produced by a lack of activity in some of the enzymes of the heme group biosynthesis is generically known as porphyria. Normally the loss of activity is produced by mutations in the amino acid sequence of said proteins and the type of porphyria depends on the specific enzyme causing the mutation. The heme group biosynthesis is shown in Scheme 1 indicating the enzymes involved in each stage of the pathway (above the reaction arrow) and detailing the names of the specific pathologies caused by functioning deficiencies in each of these enzymes (in italic form) [P=propionate, A=acetate, V=vinyl, M=methyl].

Congenital erythropoietic porphyria (CEP), also known as Günther's disease named after the author who described it in 1911, is a hereditary disease and the least frequent of the porphyrias (affecting >1 in 1000000 people). This disease is a consequence of a malfunction in the uroporphyrinogen III synthase (UROIIIS), which is an enzyme of 260 amino acid residues (in the human isoform) catalyzing the cyclization of the linear tetrapyrrole hydroxymethylbilane to produce macrocycle uroporphyrinogen III (or urogen III), the precursor of the heme groups, siroheme, F340, vitamin B12 and chlorophyll. The tetrapyrrole substrate is highly unstable and in the absence of the UROIIIS enzyme it spontaneously degrades to uroporphyrinogen I (uroporphyrinogen I and III differ only in the position of a P group and an A group in the D ring of the cycle). The cyclization of the preuroporphyrinogen for producing uroporphyrinogen III (enzymatic pathway) or uroporphyrinogen I (spontaneous degradation) is shown in Scheme 2.

Uroporphyrinogen I and its derivatives are difficult to catabolize by-products that tend to accumulate in the body. Thus, large amounts of uroporphyrinogen I which accumulate in bags below the eyes and deform the extremities are produced in CEP patients (those having a UROIIIS deficiency). Depending on its severity, other common symptoms of the disease are, for example, an extreme sensitivity to sunlight from infancy that manifests as intense dermal lesions in the exposed areas, bone and cartilage destruction, erythrodontia (dark brown coloration of the teeth, especially baby teeth due to the porphyrin accumulation), anemia, splenomegaly produced by severe haemolytic anaemia, etc.
Some compounds have been proposed as useful for the management of CEP. For instance, WO 2012/017088 discloses pyrrole and indole compounds having capacity to inhibit the catalytic activity of porphobilinogen deaminase.
Today, however, the only curative treatment for CEP that has been reported is a bone marrow transplant, i.e., replacing the bone marrow of the CEP patient (recipient) with the healthy bone marrow of another person (donor). After an effective transplant the clinical characteristics of CEP, such as photosensitivity or anemia are resolved. However, the scars from previous skin lesions are permanent. Furthermore, for a successful transplant the bone marrow of the donor must have high similarity to that of the recipient. In this sense, the bone marrow transplant is a high-risk (two deceased cases in about fifteen transplants) and powerful treatments inhibiting the recipient's immune system are initially required to prevent rejection. Due to all of this, a bone marrow transplant is reserved for those severely affected individuals having an identical bone marrow donor.
Accordingly, there is still a great need of providing therapeutic agents suitable for the treatment and/or prevention of congenital erythropoietic porphyria (CEP).